Systematic Analysis of Splice-Site-Creating Mutations in Cancer.

Journal Article (Journal Article)

For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases.

Full Text

Duke Authors

Cited Authors

  • Jayasinghe, RG; Cao, S; Gao, Q; Wendl, MC; Vo, NS; Reynolds, SM; Zhao, Y; Climente-González, H; Chai, S; Wang, F; Varghese, R; Huang, M; Liang, W-W; Wyczalkowski, MA; Sengupta, S; Li, Z; Payne, SH; Fenyö, D; Miner, JH; Walter, MJ; Cancer Genome Atlas Research Network, ; Vincent, B; Eyras, E; Chen, K; Shmulevich, I; Chen, F; Ding, L

Published Date

  • April 3, 2018

Published In

Volume / Issue

  • 23 / 1

Start / End Page

  • 270 - 281.e3

PubMed ID

  • 29617666

Pubmed Central ID

  • PMC6055527

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2018.03.052


  • eng

Conference Location

  • United States